Octalone carboxylic acids and their derivatives

ABSTRACT

THIS INVENTION RELATES TO 6,6-DIMETHYL-$9-8- OCTALONE CARBOXYLIC ACIDS AND DERIVATIVES THEREOF. THE . PRODUCTS ARE USEFUL AS PHARMACOLOGICAL AGENTS IN VIEW OF THEIR ANTIBACTERIAL, CHLORERETIC ACTIVITY, AND ABILITY TO REDUCE BLOOD CHOLESTEROL CONCENTRATIONS.

United States Patent 9 Int. Cl. (169d 27/52 U.S. Cl. 260-326 C 2 Claims ABSTRACT OF THE DISCLOSURE This invention relates to 6,6-dimethyl-A 8 octalone carboxylic acids and derivatives thereof. The products are useful as pharmacological agents in view of their antibacterial, chloreretic activity, and ability to reduce blood cholesterol concentrations.

This application is a continuation of Ser. No. 56,997, filed June 8, 1970, now abandoned, which in turn is a division of Ser. No. 389,489, filed Aug. 13, 1964, and now U.S. Pat. No. 3,532,742.

The present invention concerns a novel class of chemical products having utility as chemical intermediates and having biological activity, especially choleretic propertes. These products comprise the 6,6-dimethyl-A -8-octalone carboxylic acids corresponding to Formula I, the metal salts, and carboxyl derivatives thereof.

in which:

R is selected from the group consisting of pyridyl, phenyl,

and phenyl bearing from one to two substituents selected [from alkoxy having up to 4 carbon atoms, halogen, and hydroxyl;

X and Y are selected from the group consisting of hydrogen, phenyl, carboxyl, lower carbalkoxyl having up to carbon atoms, carboxamide groups of the formula and together form a substituent selected from the group consisting of -o o-oooand c ONCO no more than one of X and Y being selected from hydrogen and phenyl, wherein is selected from the group consisting of piperidino, morpholino, piperazino, and amino, wherein R and R are selected from the group consisting of hydrogen and lower alkyl having up to 4 carbon atoms, and

R is selected from the group consisting of hydrogen, lower alkyl having up to 4 carbon atoms, and dilower alkylaminoalkyl having up to 4 carbon atoms in the alkyl portions thereof.

The products conforming to the invention, therefore, include mono-acids, di-acids, and their functional derivatives including amides, esters, and imides.

Synthetic methods useful for the preparation of these substances are illustrated in Equations 1, 2, 3, 4, and 5 which are shown below. Specific examples of biologically active products envisaged by this invention are given later, together with processes for preparing them.

In order to obtain the derivatives (I) according to the invention, it is necessary to obtain two groups of intermediate products, the dienones (II-a), and the octalone anhydrides (II-b) which are obtained from the dienones. The latter serve as intermediates for the di-acid, ester, amide, and imide types of Formula I.

ice

cs, 0H5 ca, m

(1) a-camca, o n-ca=ca o (II- CH3 CH5 0 o colo CH-C ll :0 ca 9 co (2) 11-bit =0}! 0 Gil-00+ R R CH3 (II-a) (II-b) (114)) cu, cus 1 f CH coon CH coon n-.cu=ca o coon n J n (3) ca cu (II-B) (I-c') (I-c) O C6115 CH3 CH5 is fl Q r a u-ca=cs 0 cu I cto) (II-a) coon coca n CH CH: coon CH R o c o co-o R l coon 01!: 13 3 r. a 0H; -s)

(n'b) o coon (5) CH: coK L 01! R k a O CO" o 0045K,

I. I co c CH: R pxglnf CH R (6) We 01-! (II-b) Intermediate dienones (II-a) .-These products have the general formula shown in the table of formulas given above, in which R has the same significance as given above.

The intermediate dienones (II-a) are prepared by reacting aldehydes with 3,S,S-trimethylcyclohexenone (isophorone) in the presence of a warm dilute aqueous alkaline solution according to Equation 1.

It has been proven that in the case of benzaldehyde, the compound obtained indeed has the styryl cyclohexenone structure shown (Conia and OLeary, C. R., 249, 1002 (1959); Bull. (1960), 212).

3 EXAMPLE 1 A mixture of 350 g. of isophorone, 260 g. of benzaldehyde, and 2.0 l. of aqueous sodium hydroxide is refluxed with stirring for 5 hours. The mixture is allowed to cool and is neutralized with acetic acid; the crystalline product is collected and washed with water; there is thus obtained 48 g. of 3-styryl-5,S-dimethyl-Z-cyclohexene-1- one, M.P. 78 C. (see Conia and OLeary (loc. cit.) and Cornubert and Borel, Bull. (1929), 1158).

EXAMPLE 2 A mixture of 140.5 g. of p-chlorobenzaldehyde, 140 g. of isophorone, and 700 ml. of 5% aqueous sodium hydroxide is refluxed for 5 hours. The mixture is allowed to cool and is then neutralized with acetic acid; the prodofmaleic anhydride is heated for 2 hours on a boiling water bath. The product so obtained is dissolved in a minimum of hot benzene. On cooling, there crystallizes 5.9 g. of the anhydride 3-(o-methoxystyryl)-6,6-dimethyl- A -8-octalone-1,2-dicarboxylic acid, M.P. 167-168 C.

There is thus obtained compound No. 13 of Table 2 which follows and in which are given other examples of these intermediate anhydrides.

The anhydrides are crystalline substances, soluble in most organic solvents and giving the usual reactions of anhydrides of 1,2-dicarboxylic acids. The properties of the new intermediate compounds prepared are summarized in Table 2.

TABLE 2.--OCTALONE-LZ-DICARBOXYLIC ANHYD RIDES OF FORMULA II-b I a n e e n o a not 1s dried and recrystallized from 300 cc. of bOllll'ig No R 0 solvent oicrysmmmmn isopropanol. There is thus obtained 100 g. of 3-p-chloro- 135-136 Ethanol, ethyl tatestyryl-S,5-d1methylcyclohex-2-en-1-one, M.P. 114 C. 12" 3 8511,5 3;.{33 333 832: ethanol 13.. (2) CHaOCaHl 167-168 Do. Other intermediate dienones are given 1n Table 1 below, 14" m (a) CHIOC'H 155456 EthanoL in which the compound obtained in Example 2 is listed 15 3,4 cmo qrr, 195 Do. as No. 5:

TABLE 1.DIENONES OF FORMULA II-a Solventoi No. R Crystallization Comments 1 4 on 00 H 68 {clmlmxma }B P 22s-2e3 0 1 5mm 3 Isopropylether. 2.--. (2) CHaOCtHi 126-126 Isopropanol 3 (3) CHzOCgHi 64 Isopropyl ether 4-.-- (3,4) (CHsO)zCaH3---- 104 Ethanol 5-.-- (4) ClCaHt---- 3-114 Isopropanol... 6. (2) H00, 168 .....do

00s 4 205 Ethanol, acetic acid.

(CH20)C1OBH3 101 Isopropanol idyl 84 Dilute ethonol Hydrochloride recrystallized isopropanol, M.P.

tuted with this radical.

Intermediate octalone anhydrides (II-b).-These intermediate products are represented by Formula II-b in Equation 2.. They correspond to Formula I in which X and Y together form an anhydride group COOCO.

The anhydrides (II-b) are obtained starting from the intermediate dienones (II-a) by warming with maleic anhydride, with or without a solvent. The reaction is shown by Equation 2.

Reaction of the dienones (II-a) with dienophiles such as maleic anhydride and acrylic acid leads to derivatives of A -8-octalone, resulting from displacement of the double bond from its transitory position 4 [structure [II-b] in brackets] to position 9 corresponding to structure (II-b) (double bond conjugated with the carbonyl). Proof of the position of the double bond has been obtained by infrared spectral studies, by ultraviolet studies, and by nuclear magnetic resonance.

EXAMPLE 3 The intermediate products (II-a) and (II-b) make it possible to prepare the various compounds of Formula I covered by the invention.

Mono-acids.-These correspond to Formula I in which X=H and Y=COOH. These products are obtained as shown in Equation 3 by addition of the dienones (II-a) to acrylic acid or a derivative thereof.

As before, the double bond in the 4-position in the transient addition product (I-c') is displaced to the 9- position. The reaction is carried out by refluxing the reactants. In many cases, two isomeric acids are obtained, starting from the same reactants, according to the conditions of the reaction. These are stereoisomers which differ in the respective positions of the R and COOH groups, in relation to the ring. Both the cis and trans forms of these products are covered by the present invention. The various compounds of this group more methylcyclohex-Z-en-l-one (No. 2 in Table 1) and 2 g. specifically covered by the invention are given in Table 3.

TABLE 3.OCTALONE-2-CARBOXYLIC ACIDS OF FORMULA 1-0 Reaction conditions 1 Solvent of crystallization M.P., 0. Comments a, b Ethanol, acetic acid.-. 212-214 See Note A. a Ethyl acetate 162 Ois isomer.

b Isopropanol 204 Trans isomer. 5. -...--do 164 Cis isomer.

b Isopropanol, ethanol Trans isomer.

149 Cis isomer.

1 212 Trans isomer. b -do 211 a Methanol 252 1 The conditions of the reaction have been indicated for identification of the derivative, difierent reaction conditions leading to difierent isomers-Conditions oi the reaction: a=Heating 3-4 hours on an oil bath kept at 140 0.; b=The oil bath is heated gradually to 250 C. and is kept at this temperature for 4 hours.

NOTE A.Ethyl ester, M.P. 97C, and its oxime, M.P. 179 C. Methyl ester, M.P. 101 C. The esters are obtained by esterification oi the acid with a mineral acid, or by addition of the diene to the corresponding acrylic esters.

The compounds thus obtained are well crystallized solids, showing the general reactions of carboxylic acids, and especially can be titrated by acidimetry. Their salts with the alkali metals are soluble in water. Other metal salts, and salts with other inorganic and organic bases are prepared by neutralization in conventional fashion.

EXAMPLE 4 3-styryl-5,5-dimethyl cyclohex-2-en-1-one, g., acrylic acid, 5.0 g., and 0.1 g. of hydroquinone are refluxed for 3-4 hours (until a sample of the reaction mixture becomes soluble in dilute aqueous sodium hydroxide). The mixture is allowed to cool and the product is crystallized by addition of water. The material is filtered, washed with water, and recrystallized from acetic acid or ethanol. There is thus obtained 6.8 g. of 3-phenyl-6,6-dimethyl- A -8-octalone-2-carboxylic acid, M.P. 2l2-2l4 C. (Compound No. 16 in Table 3).

EXAMPLE 5 o-Methoxybenzylidene isophorone (Compound No. 2, Table 1), 20 g., acrylic acid, 9 g., and 0.1 g. of hydroquinone are heated for 3 hours on an oil bath kept at 130- 140 C. The mixture is allowed to cool and is then dissolved in 2 N aqueous sodium hydroxide solution. The alkaline solution is extracted with ether and the product precipitated as an oil with hydrochloric acid. The product so obtained solidifies on standing. It is collected, washed with water, and recrystallized from isopropanol. There is thus obtained 16.8 g. of cis 3-o-methoxyphenyl-6,6- dimethyl-A -8-octalone-2-carboxylic acid, M.P. 164 C. (Compound No. 19, Table 3).

EXAMPLE 6 o-Methoxybenzylidene isophorone, 20 g., acrylic acid, 9 g., and 0.1 g. of hydroquinone are heated on an oil bath. The temperature of the oil is raised gradually to 250 C. and is kept at this temperature for 4 hours. The mixture is then treated as in Example 5 and there is obtained 12 g. of the transisomer of that in Example 5, M.P. 208 C. (Compound No. 20, Table 3).

A special case is that of 3-(2-hydroxystyryl)-5,5-dimethylcyclohex-Z-en-l-one (Compound No. 6, Table 1).

Reaction of this dienone with acrylic acid at a temperature of 130-140 under reflux on an oil bath leads to the lactone of 3 (o-hydroxyphenyl)-6,6-dimethyl-A -8-octalone-Z-carboxylic acid (No. 26), M.P. 190 C. (after recrystallization from ethanol) (oxime M.P. 243 C.).

With cinnamic acid, reaction with the dienones (II-a) gives carboxylic acids of Formula I-d or I-d', the reaction being indicated by Equation 4 in the table of formulas.

The following compounds have thus been prepared: No. 27, R=C H M.P. 215 C. (after recrystallization from ethanol); No. 28, R=(3,4) (CH O) C H M.P. 168 C. (d.).

EXAMPLE 7 Cinnamic acid, g., 3-styryl-5,5-dimethyl-2-cyclohexene-l-one, 23 g., and 0.1 g. of hydroquinone are heated for 5 hours at 180 C. The mixture is allowed to cool and is dissolved by warming in its volume of benzene; on cooling there crystallizes 5 g. of cinnamic acid, which is removed by filtration. The filtrate is extracted with 2 N NaOH and the 1,3diphenyl-6,6-dimethyl-A -8-octalone- 2-carboxylic acid or its isomer of Formula I-d' is precipitated by addition of hydrochloric acid.

Di-acids.--These correspond to Formula I in which They are represented by Formula I-e. These compounds result from hydrolysis of the intermediate anhydrides (II-b) in alkaline medium.

Table 4 contains data on represenative examples of such derivatives:

EXAMPLE 8 The anhydride of 3-(o-methoxyphenyl)-6,6-dimethyl- A -8-octalone-l,Z-dicarboxylic acid, 2.0 g., prepared as in Example 3 (No. 13), and 40 cc. of 2 N sodium hydroxide are heated until a homogeneous solution is obtained. The mixture is allowed to cool and is acidified with hydrochloric acid. The product which precipitates is collected on a filter and washed with water. It is recrystallized from aqueous ethanol. There is thus obtained 20 g. of 3-(o-methoxyphenyl)-6,6-dimethyl A 8 octalone-1,2- dicarboxylic acid, M.P. 235-240 C. (No. 31, Table 4).

Esters.These compounds are prepared by reaction of the anhydrides (II-b) with alcohols (or with phenols). One can thus obtain either monoor diesters.

In certain cases, the condensation with dienophiles, which leads to the anhydrides (II-b), and the esterification can be carried out in a single step.

EXAMPLE 9 Fifteen grams of the anhydride of 3-phenyl-6,6-dimethyl-A -8-octalone-1,2-dicarboxylic acid (No. 10, Table 2) is dissolved in cc. of anhydrous ethanol; gaseous hydrogen chloride is then passed into the solution to saturation in the cold. The mixture is allowed to stand overnight and is then refluxed for 4 hours. The excess of alcohol is removed under vacuum and the residue is taken up in ether and water; it is washed with a solution of 5% sodium carbonate solution and then with water. The ethereal solution is dried over anhydrous sodium sulfate and the solvent is removed by distillation. The crystalline residue is recrystallized from petroleum ether to obtain 10 g. of 3- phenyl-6,6-dimethyl-A -8-octalone-1,2 dicarboxylic acid diethyl ester, M.P. 82 C. (No. 34).

EXAMPLE 10 The anhydride of 3-phenyl-6,6-dimethyl-A -8-octalone- 1,2-dicarboxylic acid (N0. 10, Table 2), 5 g., is dissolved in 25 cc. of anhydrous acetone; there is added to this solution 1.8 cc. of B-dimethylaminoethanol. The reaction mixture becomes hot and is then refluxed for 1 hour; the solvent is evaporated and the residue is triturated with anhydrous ether. The product is recrystallized from isopropanol by the addition of ether. There is thus obtained 4.1 g. of the Z-(fl-dimethylaminoethyl)ester of 3-phenyl- 6,6-dimethyl-A -8-octalone-1,2-dicarboxylic acid or its isomer, the l-(p-dimethylaminoethyl)-ester (No. 35), M.P. 168-170 C.

In the case of 3-(o-hydroxystyryl)-5,5-dimethylcyclohex-2-en-1-one addition of maleic anhydride and esterification of the phenolic hydroxyl group occur simultaneously.

EXAMPLE 11 (Condensation and esterification in a single step) 3-(o-hydroxystyryl)-5,5-dimethylcyclohex 2 en-lone (No. 6, Table 1), 8.6 g., maleic anhydride, 3.2 g., and 40 cc. of toluene are refluxed together. The reaction mixture is allowed to cool and is then filtered ,and there is thus obtained 7.8 g. of the lactone of 3-(o-hydroxyphenyl)-6,6-dimethyl-A -8-octalone-1,2-dicarboxylic acid, M.P. 236 C. (No. 36).

Amides.--The reaction of the anhydrides (II-b) with primary or secondary amines leads to amide acids (I-g or I-g' of Equation 5). R and R have the definition given above.

Compounds (I-g) or (I-g') so obtained have the characteristics of carboxylic acids and of amides and, in particular, can be titrated by acidimetry. As the compounds obtained are frequently mixtures of isomers, they show a rather large range of melting point. The preparation can be carried out in aqueous medium or in an organic solvent, using one or more molar proportions of the amine.

Table gives the conditions for preparation, the formulas, and the important physical properties of certain The solution is acidified with hydrochloric acid; the crystalline precipitate is collected and washed with water. It is recrystallized from ethanol to give 7.8 g. of 3-phenyl- 6,6-dimethyl-A -8-octalone 2 N methylcarboxamidel-carboxylic acid or the l-N-methylcarboxamide-2-carborylic acid, M.P. 176 C. (No. 43).

EXAMPLE 14 The anhydride of 3-phenyl-6,6-dimethyl-A-8-octa1one- 1,2-dicarboxylic acid, 3.24 g., is dissolved in 7 cc. of ethyl TABLE 5.-OCTALONE 1,2-DICARBOXYLIC ACID MONOAMIDES 0F FORMULA I-g and I-g M.P., N R R1 Technique C. Solvent recrystallization NH, b (acetone)- 190-192 Acetone. NH-CH; a

Ethanol. N H--CH(CH:4)2 Ethyl acetate, isopropauol; NH--C4Hn (4) Ethanol.

CH (acetone b (OHQCII) 195-200 Chloroiormlsopropanol; NH-(IJ-CH; 0 (0112012) 42 0.11. c (ethyl acetate).... 180 Ethyl acetate.-

43 Nwm) 170-180 Isopropanol.

44-.- CIHI N(C2Hs)2 a E%% g3?g 195-200 Isopropanol ethyl acetate. 0 (CH 01:)

45 CIHI s c (ethyl acetate).... 180-182 Ethyl acetate.

46 CeHs s b (acetone) 148-150 Isopropanol.

47 C H o (ethyl acetate 236 Ethanol} I N-CHI 48 (2) CHaOCH N(C1Hs)! b tone) 210 Isopropanol. 48A (3; CHaOCaHi N( 1Hs)z b Ha h; 180-185 Do. 49 (4 CH;OC.H4 N(C2Hs)2 b (ac tone 174 Ethanol.

1 Soluble in both acid and alkaline medium.

representative products. In this table, the letters (a), (b), and (e) have the following meanings:

(a) Preparation carried out in aqueous medium with an excess of amine (mor ethan 2 molar equivalents).

(b) (Solvent) Preparation carried out in organic medium with excess of amine (more than 2 molar equivalents).

(c) (Solvent) Preparation carried out in organic medium using one mole of anhydride to one mole of amine.

EXAMPLE 12 The anhydride of 3-phenyl-6,6-dimethyl-A -8-octa1one- 1,2-dicarboxylic acid, g., is dissolved in 50 cc. of anhydrous acetone. The mixture is chilled in an ice bath, and a current of ammonia gas is passed in until an alkaline pH is evident. The product is filtered and the pasty material is washed with acetone. It is dried in air and then dissolved in water. The mixture is filtered and acidified with hydrochloric acid solution; the precipitate is collected, washed with water, and dried in vacuo. There is thus obtained 7 g. of 3-phenyl-6,6-dimethyl-A -8-octalone- 2-carboxamide l carboxylic acid (or l-carboxamide-Z- carboxylic acid), M.P. 190-192 C. (No. 37).

EXAMPLE 13 The anhydride of 3-phenyl-6,6-dimethyl-A -8-octalone- 1,2-dicarboxylic acid, 10 g., is dissolved in 50 cc. of acetone and there is added to this solution with cooling in an ice bath and stirring, g. of a 33% aqueous solution of monomethylamine. The mixture is stirred for 1 hour. The solution becomes homogenous and then partially crystallizes; the solid is redissolved with 100 cc. of water.

acetate. There is added 0.85 cc. of piperidine and the exothermic reaction is allowed to proceed; the mixture is allowed to stand until crystallization occurs and the product is collected by filtration. There is obtained 2.6 g. of 3-phenyl-6,6-dimethyl-A -8-octalone 2 (l piperidinocarbonyl)-1-carboxylic acid or the 2-carboxylic acid-(1- piperidinocarbonyl) compound, M.P. C., (No. 45). Crystallization of this compound from ethyl acetate raises the melting point to l82 C.

Imides.-'Ihe action of primary amines, R NH on the anhydrides (II-b) gives rise, after dehydration, to the imides (Ih) shown in Equation 6.

The following representative examples of these compounds are given:

EXAMPLE 15 The anhydride of 3-phenyl-6,6-dimethyl-A -8-octalone- 1,2-dicarboxylic acid, 50 g., is suspended in 80 cc. of xylene and there is added slowly and with cooling 12 g. of n-butylamine. The reaction mixture is refluxed for 6 hrs. using a Dean-Stark trap to remove the water. The solvent is removed under vacuum. The residue is dissolved in ether and washed with 0.5 N aqueous sodium hydroxide solution and then with water. It is dried and the solvent evaporated; there is thus obtained 35 g. of oily residue which is washed with petroleum ether and recrystallized from isopropanol to give 25 g. of 3-phenyl- 6,6-dimethyl-A -8 octalone l,2-N-(n-butyl)dicarboximide, M.P. 112 C. (No. 50). The oxime of this compound melts at 177 after recrystallization from ethanol.

9 EXAMPLE 16 The anhydride of 3-pheny1-6,6-dimethyl-A -8-octalone- 1,2-dicarboxylic acid, 15 g., is treated with cooling with 4.5 g. of N,N-dimethylethylenediamine. The mixture is heated for 2 housr at 180 C. It is allowed to cool and is then dissolved in ether. The ethereal solution is washed with water and is extracted with dilute hydrochloric acid. The acid solution is made basic with sodium hydroxide and the precipitated oil is taken up in ether; this solution is dried over calcium chloride, and the hydrochloride is precipitated by passing in anhydrous hydrogen chloride gas. The product so obtained is recrystallized from 90% isopropanol to give 6.5 g. of the hydrochloride of 6,6- dimethyl-3-phenyl-A -8-octalone 1,2 [N-(fi-dimethylaminoethyl) 1dicarboximide, which melts with decomposition about 280 C. (No. '51).

The compounds of the present invention are useful as chemical intermediates in the synthesis of biologically active end products and as pharmaceutical products in their own right, in view of their antibacterial, choleretic activity, and ability to reduce blood cholesterol concentrations.

As an example of one compound of the present invention having utility as a chemical intermediate, 6,6-dimethyl-3-phenyl-A -8-octalone-'1,2-dicarboxylic acid anhydride may be mentioned. This anhydride reacts with Water, alcohol, amines, and other organic compounds to provide a variety of the corresponding carboxylic acid derivatives including esters, amides, etc.

As compounds of the present invention illustrating a useful degree of antibacterial activity, the following may be mentioned:

No. 20.6,6-dimethyl-3-(Z-methoxyphenyl)-A -8- octalone-2-carboxylic acid No. 23.6,6-dimethyl-3-(4-chlorophenyl)-A -8-octalone- 2-carboxylic acid No. 24.6,6-dimethyl-3-(Z-methoxy-5-chlorophenyl)-A 8-octalone-2-carboxylic acid.

These substances are variously effective in inhibiting the growth of the following organisms: Staphylococcus aureus, Staphylococcus No. 133, Staphylococcus pyogenes, Neisseriw gonorrheae, Diplococcus pneumoniae, Streptococcus hemolyticus, etc. The latter two substances named are superior to sulfathiazole in effectiveness against certain of these organisms. They may be administered locally in the form of solutions containing 0.2 to 10% by weight of the active ingredient.

The following substances are preferredspecies of the present invention as choleretic agents:

ticularly preferred for their choleretic activity. Compound No. 51 is more active than sodium dehydrocholate 10 and, in addition, is free of spasmolytic and antihistiminic side effects.

The compounds of the present invention may be administered parenterally and orally for therapeutic purposes in dosages of 50-500 mg. in various of the usual pharmaceutical dosage forms including tablets, solutions, capsules, suspensions, granules, etc.

The octalone is mixed with the lactose and formed into a granulation with an aqueous solution of gelatin. The dry granulation is then blended with the talc and magnesium stearate and pressed into tablets, each weighing 250 mg. and containing mg. of the active ingredient.

EXAMPLE B Solution for injection The following ingredients are employed:

6,6-dimethyl 3 phenyl-A -8-octalone-1,2-dicarboxylic acid mono N-t-butylamide sodium salt, g. 100 Sodium chloride, g. 25 Distilled water, 1. 5

A solution of the ingredients is prepared, filtered to free it of foreign material, filled into ampoules, each containing 5 cc. of this solution corresponding to 100 mg. of the active ingredient, the ampoules sealed and sterilized in an autoclave.

EXAMPLE C Topcal solution The following ingredients are employed:

6,6-dimethyl 3 (4-chlorophenyl)-A -8-octalone-2- carboxylic acid sodium salt, g. 5 Ethanol, ml. 70 Distilled water, ml. 100

This solution is then suitable for topical application in the treatment of various bacterial infections.

What is claimed is:

1. A compound having the formula wherein R is phenyl or phenyl hearing from one to two substituents selected from alkoxy having up to four carbon atoms, halogen and hydroxyl and X and Y constitute the group in which R is hydrogen, lower alkyl having up to four carbon atoms, or diloweralkylaminoalkyl having up to four carbon atoms in each alkyl portion thereof.

3,775,430 1 1 1 2 2. 6,6-dimethy1 3 phenyLM-S-octalone-1,2-[N-(p-di- JOSEPH A. NARCAVAGE, Primary Examiner methylaminoethyl) ]dicarboximide.

US. Cl. X.R.

References 260247.2 A, 247.5 B, 268 BC, 293:6 Z, 346.3, 515 R; UNITED STATES PATENTS 5 424308, 317

3,440,248 4/1969 Roberts et a1 260326 C 

